Novel cyclosporin analogue, ISATX247, is a mixture of cis and trans isomers of cyclosporin diene analogue, which is chemically described as cyclo {(E,Z)-(2S,3R,4R)-3-hydoxy-4-methyl-2-(methylamino)-6,8-nonadienoyl-L-2-aminobutyryl-N-methyl-glycyl-N -methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl}. It is remarkable that the mixture of ISATX247 isomers exhibits a combination of enhanced potency and reduced toxicity over natural cyclosporins and presently known cyclosporin derivatives (Abel et al., “ISATX247: A Novel Calcineurin Inhibitor,” J. Heart Lung Transplant, 20:161 (2001); Aspeslet et al., “ISATX247: A Novel Calcineurin Inhibitor,” Transplantation Proceedings, 33:1048-1051 (2001); U.S. Pat. Nos. 6,605,593 and 6,613,739 to Naicker et al.).
ISATX247, as a mixture of cis and trans isomers, is currently being co-developed by Roche and Isotechnika for treatment of multiple diseases. The drug candidate has successfully completed a phase II clinical trial for psoriasis and achieved positive results in one phase II (phase IIa) clinical trial for kidney transplantation. The main phase IIb clinical trial in kidney transplantation is due to begin soon.
In the course of the collaboration between Roche and Isotechnika for the clinical development and commercialization of ISATX247, a formulation of the trans ISATX247 (the trans-isomer of ISATX247) has been developed. Based on a restructured collaboration between the two companies, clinical trials for both kidney transplantation and treatment of psoriasis by such formulations of trans ISATX247 are under way. Compared to the corresponding cis-isomer, the trans-isomer of ISATX247 (trans ISATX247) has shown better activity on immunosuppression and improved therapeutic index. The interesting biological properties and the potential pharmaceutical utility of trans ISATX247 make it important to develop new methods for stereoselective synthesis of this drug candidate.
There are several synthetic pathways known in literature for the preparation of ISATX247 as a mixture of cis and trans isomers, some of which involving a Wittig reaction of either acetyl cyclosporin aldehyde or triphenylphosphonium bromide of acetyl cyclosporin A (U.S. Pat. Nos. 6,605,593 and 6,613,739 to Naicker et al.; PCT International Publication Nos. WO 03/033526 and WO 03/033527 to Naicker et al.). However, only very few methods for stereoselective synthesis of the trans-isomer of ISATX247, such as the application of Peterson olefination, have been developed (PCT International Publication Nos. WO 03/033526 and WO 03/033527 to Naicker et al.).
The present invention is directed to overcoming these deficiencies in the art.